The development of the tetracycline antibiotics was the direct result of a systematic screening of soil specimens collected from many parts of the world for evidence of microorganisms capable of producing bactericidal and/or bacteriostatic compositions. The first of these novel compounds was introduced in 1948 under the name chlortetracycline. Two years later, oxytetracycline became available. The elucidation of the chemical structure of these compounds confirmed their similarity and furnished the analytical basis for the production of a third member of this group in 1952, tetracycline. A new family of minocycline compounds, without the ring-attached methyl group present in earlier tetracyclines, was prepared in 1957 and became publicly available in 1967; and minocycline was in use by 1972.
Recently, research efforts have focused on developing new tetracycline antibiotic compositions effective under varying therapeutic conditions and routes of administration. New tetracycline analogues have also been investigated which may prove to be equal to or more effective than the originally introduced minocycline compounds. Examples include U.S. Pat. Nos. 2,980,584; 2,990,331; 3,062,717; 3,165,531; 3,454,697; 3,557,280; 3,674,859; 3,957,980; 4,018,889; 4,024,272; and 4,126,680. These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions.
Historically, soon after their initial development and introduction, the tetracyclines were found to be highly effective pharmacologically against rickettsia; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis. Hence, tetracyclines became known as “broad spectrum” antibiotics. With the subsequent establishment of their in vitro antimicrobial activity, effectiveness in experimental infections, and pharmacological properties, the tetracyclines as a class rapidly became widely used for therapeutic purposes. However, this widespread use of tetracyclines for both major and minor illnesses and diseases led directly to the emergence of resistance to these antibiotics even among highly susceptible bacterial species both commensal and pathogenic (e.g., Pneumococci and Salmonella). The rise of tetracycline-resistant organisms has resulted in a general decline in use of tetracyclines and tetracycline analogue compositions as antibiotics of choice. In addition, other antibacterial agents have also been over used creating strains of multiple drug resistant bacteria. Therefore, there is a need for effective antibacterial agents for the treatment of bacterial infections in general, particularly antibacterial agents with no or less severe resistance by disease-responsible pathogens.
Urinary tract infections (UTIs) are bacterial infections of the urinary tract and are one of the most common conditions for which patients are prescribed antibiotics (Mazzulli, The Canadian Journal of Urology 19(s1):42-48, 2012). When it affects the lower urinary tract, it is known as a simple cystitis (a bladder infection). When it affects the upper urinary tract, it is known as pyelonephritis (a kidney infection). Symptoms from a lower urinary tract include painful urination and either frequent urination or urge to urinate (or both); while the symptoms of pyelonephritis include fever and flank pain in addition to the symptoms of a lower UTI. In some cases, a painful burning sensation in the urethra may be present even when not urinating.
UTIs are fairly common in the general population with nearly 50% of women (and 12% of men) having at least one UTI in their lifetime, making UTIs the most common bacterial infection in women. UTIs have a high recurrence rate with about 25% of women experiencing a second episode within 6 months of their first UTI (Foxman, Disease-a-Month 49(2):53-70, 2003). About 15% of all community-prescribed antibiotics in the US are dispensed for UTIs, which is estimated to total over $1 billion annually. Direct and indirect costs due to UTIs total $1.6 billion annually.
UTIs are categorized into uncomplicated and complicated UTIs (cUTI). Uncomplicated UTIs are usually diagnosed in healthy premenopausal women with normal functioning urinary tracts. cUTIs are found in patients with structural or functional abnormalities in their urinary tract who may possess other underlying risk factors such as antibiotic-resistant organisms, comorbid illnesses, or recurrent UTIs. In addition, if a urinary tract infection involves the upper tract, and the person has diabetes mellitus, is pregnant, is male, or immunocompromised, it is considered complicated. To diagnose either an uncomplicated or complicated UTI, a clinician must perform a history and a physical examination and send samples for urinalysis. Acute symptoms consist of urinary frequency, pain or burning on urination, urgency, or foul smelling or cloudy urine. More severe UTIs that involve the upper urinary tract can present additionally with patient discomfort, flank pain, and fever.
Although urine cultures are not always performed with uncomplicated UTIs, they are mandatory when a cUTI is suspected. The presence of certain biomarkers such as nitrites and leukocyte esterase in the urine are indicators of UTIs. If the infection is suspected to have spread to the kidneys, urine cultures are then recommended. Urine cultures are also recommended for patients whose symptoms do not resolve or recur 2-4 weeks after treatment. Computed tomography (CT) or ultrasound scans are usually performed to rule out correctable, anatomical causes of cUTIs. If UTIs are left untreated or are treated inadequately, patients can develop complications such as recurrent infections, renal failure, or sepsis (Nicolle, The Canadian Journal of Infectious Disease and Medical Microbiology 16(6):349-360, 2005).
There are approximately 7 million and 0.9 million uncomplicated and complicated UTI cases each year. Quality of life is affected and daily activity is interrupted, with the patient missing work or school due to UTIs.
The pathogen responsible for nearly all UTIs is uropathogenic Escherichia coli (UPEC), which is isolated in greater than 75% of cases. Complicated UTIs (cUTIs) have more varied, less predictable bacterial etiologies, although UPEC is still found in roughly 50% of cases. Pathogens responsible for cUTIs, including MRSA, methicillin-resistant coagulase-negative staphylococci (MRCoNS), vancomycin-resistant enterococci (VRE), and bacteria producing extended spectrum beta lactamases (ESBLs), tend to be more resistant to current antibiotic therapies (Pallett and Hand, Journal of Antimicrobial Chemotherapy 65(s3):iii25-33, 2010). The most common route of infection is for UPEC to enter the urethra and ascend into the bladder. After infection, UPEC migrate into deeper urothelial layers and proliferate intracellularly in clusters, eventually forming biofilms capable of defending against the body's immune response.
As to treatment, IDSA recommends co-trimoxazole twice daily for three days as the first line treatment for uncomplicated UTIs in premenopausal women. Alternatives to co-trimoxazole include nitrofurantoin, amoxicillin-clavulanic acid, cephalosporin, fosfomycin, ofloxacin, and ciprofloxacin. Unfortunately, bacteria have exhibited increasing resistance against these first- and second-line antibiotics. Beta-lactam antibiotics are no longer recommended as a first-line therapy because E. coli resistance rates now exceed 20%. Fluoroquinolones have lower resistance rates, under 10%, but these resistance rates have been trending upward.
Treatment for cUTIs, however, is not as clearly defined. Currently, recommendations for first-line antibiotics in treating cUTIs are IV therapy with a fluoroquinolone, a carbapenem, a third generation cephalosporin, or piperacillin-tazobactam. Resistance to co-trimoxazole is seen in most cases of cUTIs so it is not recommended. For patients with sepsis most likely caused by ESBL-producing bacteria, imipenem or meropenem is recommended. In recent years, the efficacy of cephalosporins and piperacillin-tazobactam has decreased due to rising resistance, leaving few treatment options when resistant pathogens are present.
The FDA has approved several antibiotics specifically for cUTIs, DORIBAX (doripenem) in 2007, ZERBAXA (ceftolozane/tazobactam) in 2014, and AVYCAZ (ceftazidime-avibactam) in 2015. Several other marketed drugs (such as Levofloxacin, ertapenem, ceftriaxone, ceftazidime, imipenem/cilastatin) also have cUTI indications in their product labels/full prescribing information. Although DORIBAX is stable to beta-lactamases, it is labile to carbapenemases. This drug also carries a low risk of seizures, which is common to the carbapenem family, and increases the risk of C. difficile infections. ZERBAXA carries a warning of reduced effectiveness in patients with kidney impairment, which may limit its use in the most severe cUTI cases.
Further complicating the treatment of UTI is the fact that many antibiotics bind proteins, thus severely limiting their bioavailability in the unitary tract and their effectiveness against UTI. For example, glycylcyclines are a new class of antibiotics derived from tetracycline. Glycylcyclines (such as tigecycline and eravacycline) are specifically designed to overcome two common mechanisms of tetracycline resistance—resistance mediated by acquired efflux pumps and/or ribosomal protection. Presently, tigecycline is the only glycylcycline approved for clinical use. Although the precise mechanism is unclear, tigecycline has been observed to exhibit increased protein binding with increasing tigecycline concentrations. At tigecycline concentrations of 0.1 and 1.0 μg/mL, protein binding was 71% and 87%, respectively, as determined by use of an ultrafiltration technique, and was 73% and 79%, respectively, as determined by use of ultracentrifugation (Meagher et al., Clinical Infectious Diseases Vol. 41, Supp. 5: S333-S340, 2005). This apparent limitation in bioavailability in the urinary tract is further compounded by the inability to increase dose, partly due to the many undesirable side effects associated with tetracycline class antibiotics such as nausea, vomiting, diarrhea, and other GI tract adverse events (AEs).
Another glycylcycline, eravacycline, was recently announced to have failed to achieve its primary endpoint of statistical non-inferiority compared to the comparator drug levofloxacin, in the IGNITE2 phase 3 clinical trial of eravacycline administered as an IV to oral transition therapy for the treatment of complicated urinary tract infections (cUTI). This is despite the previously reported positive data from the IGNITE1 phase 3 clinical trial of eravacycline administered intravenously (IV) in complicated intra-abdominal infections (cIAI) which did meet its primary endpoint (Tetraphase Press Release, Sep. 8, 2015).
The developer of the candidate drug eravacycline—Tetraphase Pharmaceuticals—has since shown analysis that subjects treated with IV alone, or stayed on IV longer, responded better than those switching to oral, suggesting that the failed clinical trial is likely due to insufficient exposure with the oral formulation. Tetraphase has also announced plans to conduct an IV only cUTI study.
Thus overall, resistant bacteria have complicated the treatment landscape for UTIs. Due to the co-expression of resistance mechanisms, these bacteria may also be resistant to non-beta lactam antibiotics like fluoroquinolones, trimethoprim, and gentamicin. Increasing resistance has led clinicians to rely on older drugs that are less effective and often carry greater safety risks. Alternative options are limited highlighting the need for next generation treatments for cUTIs.
Furthermore, there are no oral antibiotics that are reliably effective treatments for UTI in the current environment of antibiotic resistance in uropathogenic bacteria. Current treatment may require the use of intravenous (IV) drugs, which necessitates hospital visits and drives up the total cost of treatment, not to mention the relative inflexibility in dosing options. The vast majority of physicians recognize the need for an oral antibiotic solution to this problem and an effective oral antibiotic that does not sacrifice safety would likely be widely used.